HIV-1Nef is a 27-34 kDa myristoylated protein that has multiple activities defined in vitro. These include: alterations in signaling with disruption of pro-apoptotic pathways; increased viral infectivity; T cell activation; CD28, CD4 and MHC-I downmodulation and protection of infected primary T cells form CTL lysis. Based on in vivo studies, it is known that an intact nef gene is necessary for the timely development of AIDS, and in infected monkeys, the ability of Nef to downmodulate MHC-I is an important component of Nef's in vivo activities. The mechanism used by Nef to downmodulate MHC-I remains unknown. Our data indicates that, in T cells, Nef binds the MHC-I cytoplasmic tail, prevents it from being phosphorylated and disrupts MHC-I transport from the trans-Golgi network to the plasma membrane. Studies are proposed to better understand the detailed molecular mechanism of MHC-I downmodulation. These studies should aid in the development of inhibitors that disrupt HIV immune evasion.